1. Field of the Invention
This invention provides a superior method for the removal of the p-nitrobenzyl (pNB) ester group from cephalosporin carboxylic acids. The process is economically important, because cephalosporin antibiotics are often processed in the form of pNB esters, since the esters are convenient and economical to handle in chemical processing. The ester group must eventually be removed, however, because the cephalosporins are used as pharmaceuticals in the acid or salt form.
The pNB ester group has been used in the manufacture of cephalosporins for some time. See U.S. Pat. No. 3,632,850, of Garbrecht. The pNB group has been removed chemically, such as with zinc and a strong acid, or catalytically, as taught by Garbrecht. Other deesterification methods have since been devised, such as the methods of Hatfield, using zinc and an .alpha.-hydroxycarboxylic acid, U.S. Pat. No. 4,091,214, or zinc and an organothiol, Belgian Pat. No. 856,288, and the method of Jackson, U.S. Pat. No. 3,799,924, using a dithionite salt.
All of the chemical and catalytic methods of deesterification, however, have the disadvantage that they may affect functional groups of the molecule other than the pNB ester. Indeed, the art suggests that reductive deesterification of cephalosporins having certain 3-substituent groups would reduce and cleave the 3-group, as well as the ester group. U.S. Pat. Nos. 3,792,995, of Ochiai, 4,008,228, of Chauvette, and 4,042,472, of Hall, show the reductive cleavage of such 3-groups to form 3-methyl or 3-exomethylene compounds. Hall and Ochiai show that electrolytic reduction can have that effect. Chauvette and Ochiai show such reductive cleavage without affecting ester groups, and Chauvette teaches that the pNB ester group will be unaffected while such a reductive cleavage is carried out.
2. State of the Art
The electrochemical art is well-developed, and the literature contains many examples of electrolytic reductions, some of which deal with the removal of protecting groups by electrolytic processes. Among such articles may be mentioned those by Mairanovsky, Angew. Chem. Int. Ed. Engl. 15 (5), 281-92 (1976), which describes in general terms the removal of carboxy-protecting groups, including the pNB group, from some carboxylic acids. Another pertinent article is that by Semmelhack and Heinsohn, J. Am. Chem. Soc. 94, 5139-40 (1972), which concerns the electrolytic removal of haloethoxy ester groups from carboxylic acids.